Osteoporosis is the most common metabolic bone disease, afflicting 8-10 million Americans and placing another 25 million individuals at risk. Bisphosphonates represent a class of drugs that have proven quite effective in the treatment of osteoporosis and related diseases. Unfortunately, bisphosphonate consumption is associated with GI inflammation, erosions and ulceration, by topically injuring the tissue. Our preliminary results indicate that these drugs rapidly attenuate the hydrophobic phospholipidic barrier of the stomach of rats. Based upon these observations, Natural Therapeutics is developing unique formulations of bisphosphonates and phosphatidylcholine (PC) that have a significantly lower gastric toxicity than the unmodified dtug(s) in an established rodent model system 1n this Phase I application we propose to build upon our encouraging preliminary data in the evaluation and comparison of gastric macroscopic and microscopic injury/inflammation, bleeding (hematocrit and intraluminal hemoglobin), surface hydrophobicity and apoptotic index in rats administered one of three commercially available bisphosphonates (pamidronate, alendronate and risedronate) alone and in combination with PC. We will also compare different grades of PC, ranging from 15% to 93% purity, as well as different bisphosphonate: PC ratios to determine the optimum and least costly formulation to limit the GI sideeffects of these powerful drugs. PROPOSED COMMERCIAL APPLICATION: The market for GI-safe Bisphosphonates, such as pamidronate, alendronate, and risedronate, to treat osteoporosis will be enormous.